CN114903840A - Low-dose R-ketamine intranasal medicament for treating depression - Google Patents
Low-dose R-ketamine intranasal medicament for treating depression Download PDFInfo
- Publication number
- CN114903840A CN114903840A CN202210103771.8A CN202210103771A CN114903840A CN 114903840 A CN114903840 A CN 114903840A CN 202210103771 A CN202210103771 A CN 202210103771A CN 114903840 A CN114903840 A CN 114903840A
- Authority
- CN
- China
- Prior art keywords
- ketamine
- nasal
- treatment
- depression
- medicament
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960003299 ketamine Drugs 0.000 title claims abstract description 96
- 239000003814 drug Substances 0.000 title claims abstract description 78
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 claims abstract description 58
- 238000011282 treatment Methods 0.000 claims abstract description 48
- 239000007922 nasal spray Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 39
- 229940097496 nasal spray Drugs 0.000 claims abstract description 34
- 208000020401 Depressive disease Diseases 0.000 claims abstract description 19
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 13
- VCMGMSHEPQENPE-BTQNPOSSSA-N (2r)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O VCMGMSHEPQENPE-BTQNPOSSSA-N 0.000 claims description 12
- 239000007923 nasal drop Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 229940100662 nasal drops Drugs 0.000 claims description 7
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- 206010042458 Suicidal ideation Diseases 0.000 claims description 3
- 208000024714 major depressive disease Diseases 0.000 claims description 3
- 230000003542 behavioural effect Effects 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- 230000003442 weekly effect Effects 0.000 claims description 2
- 239000006174 pH buffer Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 229960004184 ketamine hydrochloride Drugs 0.000 abstract description 12
- 206010013663 drug dependence Diseases 0.000 abstract description 2
- 238000001556 precipitation Methods 0.000 abstract description 2
- 208000011117 substance-related disease Diseases 0.000 abstract description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 16
- 230000009182 swimming Effects 0.000 description 16
- 241000700159 Rattus Species 0.000 description 14
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 9
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 5
- VCMGMSHEPQENPE-ZOWNYOTGSA-N esketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1[C@@]1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-ZOWNYOTGSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229960000450 esketamine Drugs 0.000 description 3
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- YQEZLKZALYSWHR-CYBMUJFWSA-N (R)-(+)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O YQEZLKZALYSWHR-CYBMUJFWSA-N 0.000 description 1
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- 102000003678 AMPA Receptors Human genes 0.000 description 1
- 108090000078 AMPA Receptors Proteins 0.000 description 1
- 102000003780 Clusterin Human genes 0.000 description 1
- 108090000197 Clusterin Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002635 electroconvulsive therapy Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 229960001800 nefazodone Drugs 0.000 description 1
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960002416 venlafaxine hydrochloride Drugs 0.000 description 1
- QYRYFNHXARDNFZ-UHFFFAOYSA-N venlafaxine hydrochloride Chemical compound [H+].[Cl-].C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 QYRYFNHXARDNFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Neurosurgery (AREA)
- Otolaryngology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicines, and discloses a low-dose R-ketamine nasal medicine for treating depression, which is compared with the marketed S-ketamine hydrochloride nasal spray SPRAVATO, and in single treatment, the R-ketamine nasal medicine only contains or only needs to give half of the administration dose or the content of active ingredients. The R-ketamine nasal drug with reduced dose can keep the depression treatment effect of the S-ketamine hydrochloride nasal spray before dose reduction, and has excellent clinical advantages of low dose, such as: the frequency of administration is reduced, and only one administration is needed for single treatment, so that the traditional Chinese medicine is easier to use clinically; the concentration of the active ingredient can be kept lower under the low dosage requirement, so that the problem of precipitation caused by the influence of factors such as temperature difference, shaking or storage time and the like due to the overhigh concentration of the active ingredient similar to the S-ketamine nasal spray is solved; low doses of R-ketamine nasal drug also reduced drug dependence clinically to a lesser extent.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a low-dose R-ketamine nasal medicine for treating depression.
Background
Ketamine, an NMDA receptor antagonist, was developed by Parvin Davis Lab in 1963 in its racemate injection dosage form and was approved by the FDA for use in anesthetics in 1970. The racemic injection of ketamine is the most common use form of the prior medicinal ketamine, and a plurality of medicinal enterprises and products of the same variety are approved to be sold on the market in China.
BRISTOL MYERS CO in the patent application GB1330878A discloses compounds of both the levorotatory and dextrorotatory optical isomers of ketamine, and methods for their resolution. The separated S-ketamine is also called S-ketamine, esketamine and esketamine, and the R-ketamine is also called R-ketamine and R-ketamine.
Regarding S-ketamine, Janssen corporation developed a nasal spray formulation for the indication of refractory depression. The drug is approved by FDA two breakthrough therapies, one for drug-resistant depression (2013) and the other for major depression with severe suicidal tendency (2016). The drug is currently approved by FDA in the United states under the trade name SPRAVATO. According to the SPRAVATO pharmaceutical label record: 1. each SPRAVATO device contained 2 nasal sprays providing 28mg S-ketamine hydrochloride (as free S-ketamine). A single therapeutic dose of SPRAVATO is 56mg or 84mg, requiring 2 or 3 SPRAVATO devices to support, respectively. 3, when the SPRAVATO is administrated, 1 piece of SPRAVATO equipment is taken to respectively spray 14mg of S-ketamine to two nostrils of the patient, and after the interval of 5min, another 1 piece of new SPRAVATO equipment is taken to respectively spray 14mg of S-ketamine to two nostrils of the patient again; optionally, after another 5min interval, repeat the pre-dosing step with the 3 rd SPRAVATO device to meet the 84mg dose. The formula of the SPRAVATO comprises S-ketamine hydrochloride, citric acid monohydrate, disodium edetate, sodium hydroxide and water for injection, wherein the pH of the solution is 4.5, and the specification of an active ingredient is 28mg/0.2 mL.
Speravato orange peel patents US8785500 and US9592207 disclose: 1. nasally administered ketamine can treat treatment-resistant depression that is manifested by no treatment effect using two or more of the traditional drugs/treatments including atypical antipsychotics, benzodiazepines, bupropion, electroshock therapy, lamotrigine, lithium, monoamine oxidase inhibitors, selective norepinephrine reuptake inhibitors, selective 5-hydroxytryptamine reuptake inhibitors, tricyclic antidepressants, valproic acid, nefazodone, trazodone, and pramipexole. And various criteria for the determination of treatment resistant/intractable depression are given in the detailed description section. 2. The administration dosage is 0.1-3 mg/kg/day (US 8785500). Or at a dose of 0.13 to 0.53 mg/kg/day (US 9592207).
The main technical research of the Janssen company around S-ketamine also relates to the relevant disclosures of patents CN104519878A, CN 105073096A, CN105073103A, CN106714789A, CN107208133A, CN107735081A, CN111297803A, US20200009081A 1. CN104519878A discloses: in a method of treating refractory or treatment-resistant depression, esketamine is administered in an amount in the range of about 0.01mg/kg to about 1.5mg/kg, in an amount in the range of about 0.01mg/kg to about 0.75mg/kg, or in an amount in the range of about 0.05mg/kg to about 0.5 mg/kg. CN 105073096A and CN105073103A disclose: in an S-ketamine hydrochloride nasal spray, the S-ketamine hydrochloride is present at a concentration in the range of 100mg/mL equivalent to 200mg/mL equivalent, 125mg/mL equivalent to 150mg/mL, or 126mg/mL to 162 mg/mL; the solution pH is adjusted to 3.5 to 6.5, or 4.5 to 5.5. An S-ketamine hydrochloride nasal spray formulation is formulated with S-ketamine hydrochloride present in an amount of about 161.4mg/mL, citric acid monohydrate present in an amount of about 1.5mg/mL, disodium edetate present in an amount of about 0.12mg/mL, sodium hydroxide present in an amount sufficient to adjust the pH of the pharmaceutical composition to a pH of about 4.5, and water. Treatment regimens for depression of related specific genotypes are disclosed in CN106714789A and CN 107208133A. CN107735081A, CN111297803A and US20200009081a1 investigated the dosing of S-ketamine hydrochloride nasal spray formulations and related dosing regimens.
Regarding R-ketamine, the company Henry, Jiangsu, China is also developing nasal spray formulations for depression. According to the phase I clinical test of CTR20191785 disclosed by Chinese medicine clinical test registration and information disclosure platform, the active ingredient of the Henry R-ketamine nasal spray is (R) -ketamine hydrochloride.
The patent WO2015037248 of CHIBA UNIVERSITY carries out the comparative study of R-ketamine injection and S-ketamine injection on the mouse animal experiment with potential treatment potential of depression, and discloses that the R-ketamine injection has similar efficacy compared with the S-ketamine injection, but the R-ketamine injection does not damage the pulse inhibition of mice, has the potential advantage of lower side effect and is accompanied with the characteristic of low dependence of potential medication.
In conjunction with the above background, there are two distinct technical directions for the current ketamine isomers with respect to the treatment of depression. This is mainly due to the current pathogenesis of depression and the mechanism of action of ketamine on depression treatment that is not fully elucidated.
The Janssen company developing S-ketamine isomers believes that the therapeutic effect of ketamine on depression is mainly due to its antagonistic effect on NMDA receptors, whereas S-ketamine isomers have greater potency and affinity for NMDA receptors than R-ketamine isomers, and thus have a greater therapeutic effect on depression (see CN104519878A), which potentially allows for lower doses. Based on this, Janssen company developed a nasal spray formulation with S-ketamine isomer as an active ingredient.
It is generally accepted that S-ketamine has a stronger affinity for NMDA receptors than R-ketamine, but the mechanism of action of NMDA receptors and depression therapy, including CHIBA unicity, is different from Janssen' S opinion. The neuroscient team of Mark Rasenick conducted an antidepressant drug trial in artificially cultured mouse glial cells, and the results showed that other drugs that block NMDA receptors did not exhibit the similar effects of ketamine, with no therapeutic potential for depression; and all depression treatment drugs tested by researchers resulted in a positional change of a clusterin on the glial cell membrane, directing the cells to form new junctions with their neighbors, ketamine achieved this effect within 15 minutes, which is three days for other commonly used antidepressants. This means that the ability of ketamine to block NMDA receptors is probably not a major weapon for its resistance to depression. Carlos Zarate 2016, published in Nature, J.A.A.introduces perhaps a breakdown product of ketamine to alleviate depression in mice, rather than ketamine itself. The protein affected by this compound is the AMPA receptor, not the NMDA receptor. CHIBA unicersity recognizes S-ketamine as having a greater affinity for the NMDA receptor, and in the mouse experiments it disclosed that R-ketamine hydrochloride injection has tested the same or slightly higher potential therapeutic efficacy for depression than S-ketamine hydrochloride injection. However, due to the high affinity of S-ketamine for NMDA receptors, S-ketamine drugs may have adverse effects such as drug dependence.
In summary, the current ketamine variety for the treatment of depression has been approved for sale (FDA) as S-ketamine nasal spray. The nasal preparation of R-ketamine was only reported in Henry of Jiangsu and no relevant detailed research data was published. Janssen corporation disclosed some relevant research data on S-ketamine nasal spray formulations, and R-ketamine for treatment of depression was only disclosed in small, nasal studies at the standard dosage of the original ketamine injection formulation.
Further investigation has found that the S-ketamine nasal spray of Janssen requires a high dose of 56 or 84mg for a single treatment, which is limited by the solubility of the active ingredient, and the like, 2-3 devices are required for the patient to use simultaneously for each treatment, 4-6 nasal spray operations are required, and at least 5min is required for the interval between every two devices, which is quite complicated. Due to the reason of single treatment administration requirement, even if a plurality of devices are dispersed for administration, the S-ketamine in a single device still keeps high concentration, and the research on SPRAVATO products of Janssen company discovers that under normal placement, under the influence of factors such as temperature difference, shaking or storage time, the solution in the device has the possibility of generating the condition of active ingredient precipitation, and the instability affects the medicine quality and brings great hidden danger to clinical medication. Meanwhile, ketamine is a tube product which is easy to cause dependence, and the application of high-dose S-ketamine in S-ketamine nasal spray of Janssen company is easy to bring about the risk of side effect with increased medication dependence.
Disclosure of Invention
In order to solve the above problems of the prior art, the present invention aims to provide a nasal preparation of R-ketamine.
The invention has unexpectedly found in experiments that the treatment effect of the nasal preparation of R-ketamine is significantly improved compared to the treatment effect of the nasal preparation of S-ketamine in the treatment of depression. In particular, half the amount of R-ketamine nasal preparation can achieve the full dose of S-ketamine nasal preparation. Based on this, the present invention develops low dose R-ketamine nasal drugs. Low dose techniques can bring significant clinical advantages without reducing drug efficacy.
In practicing the present invention, the technical solution of nasal administration of low dose R-ketamine in connection with the present invention can be achieved in the following manner, in combination with the use of the existing S-ketamine nasal spray, based on the unexpected findings and technical conception of the present invention as described above.
Use of R-ketamine or a salt thereof for the preparation of a nasal medicament for the treatment of depression having a lower dosing dose and/or active ingredient content than S-ketamine depression treatment administered nasally, in particular having half the dosing dose and/or active ingredient content than S-ketamine depression treatment, preferably in the form of nasal drops or nasal sprays.
In the present invention R-ketamine is preferably administered as the hydrochloride salt.
In practice, for a single treatment with a nasal drug, 14 to 56mg of R-ketamine is administered, optionally 14 to 42mg, preferably 25 to 45mg or 28 to 42mg of R-ketamine is administered, more preferably 20 to 25mg, 25 to 30mg, 30 to 35mg, 35 to 40mg, 40 to 45mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 42mg or 45mg of R-ketamine is administered.
The nasal medicine can be prepared into a form that all required therapeutic agents are administered to any one nostril of a patient in a single time during each treatment; it can also be made in such a manner that all the required therapeutic agents are administered to any nostril of the patient in two separate administrations at each treatment.
The nasal drug optionally comprises R-ketamine nasal spray or nasal drops in a single dose or multi-dose formulation, wherein each R-ketamine nasal spray or nasal drop device contains the dose required for a single treatment, and each R-ketamine nasal spray or nasal drop device contains the dose required for more than two treatments. Preferably, the nasal medication comprises a nasal spray or nasal drops of R-ketamine as a single dose formulation.
The nasal drug is administered for a single treatment with a dosage of 0.005-1.5 mg/kg, 0.005-0.75 mg/kg or 0.05-1.5 mg/kg, optionally 0.05-0.75 mg/kg or 0.065-0.265 mg/kg.
The invention also provides a corresponding R-ketamine nasal medicament for the treatment of depression, which may be the nasal medicament described in the aforementioned application. The nasal spray can also comprise a drug label and R-ketamine nasal spray, wherein the drug label comprises R-ketamine which is described in the specification of 14-56 mg, 14-42 mg, 25-45 mg, 28-42 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 42mg or 45mg for controlling single treatment administration of a patient by using 1 or more R-ketamine nasal sprays; optionally, the drug label further comprises a record that all the required therapeutic agents are administered to any nostril of the patient at one time or two or more times respectively in a single treatment. The R-ketamine nasal spray mainly comprises an R-ketamine solution and a nasal spray device, wherein the R-ketamine solution is mainly prepared from R-ketamine or a salt thereof, a pH buffering agent, a stabilizing agent, a pH adjusting agent and water. The R-ketamine solution is further formulated primarily from (R) -ketamine hydrochloride, citric acid, EDTA-2Na, sodium hydroxide, and water. The medicine label is a part of the whole medicine product, is usually packaged in a medicine packaging material together with medicine medicaments, and is also called a medicine specification, a concise description and the like on different occasions.
On the basis of the concept of the invention, correspondingly, the treatment of depression can adopt the following method, in each treatment, the effective amount of R-ketamine is nasally administered to the patient, and the effective amount is 14-56 mg, 14-42 mg, 25-45 mg, 28-42 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 42mg or 45 mg; the effective amount is especially 40-60 mg, 42-56 mg, 40mg, 42mg, 45mg, 56mg or 60mg for major depressive disorder patients with severe suicidal ideation or behavioral depression symptoms. Alternatively, following initial therapeutic administration of an effective amount of R-ketamine: administering an effective amount of R-ketamine 2 times a week for 1-4 weeks; administering an effective amount of R-ketamine 1 time per week for 5-8 weeks; on and after week 9, 1 effective amount of R-ketamine was administered weekly or 1 effective amount of R-ketamine was administered every 2 weeks.
Optionally, the depression referred to in this invention may be selected as a treatment resistant or treatment resistant depression as defined in the drug label of the S-ketamine nasal spray SPRAVATO by Jassen or related patents, and in particular, as described in the drug label of SPRAVATO.
Detailed Description
The present invention is further illustrated below with reference to specific examples.
Example (b): rat forced swimming influence experiment
1. The purpose of the experiment is as follows:
a Wistar rat forced swimming test method is adopted, whether the tested substance has the antidepressant effect is evaluated in a nasal drop administration mode, and isomers and the antidepressant effect strengths of different doses of the isomers are compared.
2. Medicine preparation:
1) test substance and blank solvent
(R) -ketamine hydrochloride solution: 132mg/ml (calculated as free base), 5 ml/tube; 66mg/ml (calculated as free base), 5 ml/tube; 33mg/ml (calculated as free base), 5 ml/tube.
(S) -ketamine hydrochloride solution: 66mg/ml (calculated as free base), 5 ml/tube.
Blank solvent: 5 ml/tube
The compositions of the test substances and the blank vehicle are shown in table 1 below.
TABLE 1
Note: "/" indicates that the substance was not added.
Preparation of test substance and blank solvent: weighing the raw and auxiliary materials, adding the raw and auxiliary materials into purified water with the formula amount, dissolving and mixing uniformly, and adjusting the pH to 4.5 by using 0.1mol/L sodium hydroxide solution to obtain the product.
2) Positive drug
Venlafaxine hydrochloride sustained release capsules (Yinuosi), 150 mg/capsule, 7/tablet, 2/tablet/box, manufactured by Pfizer, commonly available commercially.
Preparing positive drugs: adding 0.5% CMC-Na into 1 capsule (150mg), adding water for injection to 25mL, ultrasonic treating, and vortex mixing.
3. An experimental instrument:
the name of The PhenoTyper
Model number PhenoTyper model 3000
Sources Noldus Information Technology, Wageningen, Netherlands.
4. Experimental animals:
wistar rats, SPF grade, sourced from shanghai slyke laboratory animals.
Animal body weights at the start of the experiment: about 220g, 5-7 days of normal environmental adaptation period, completely randomly grouping, and 10 in each group.
5. Experimental groups and dosage
Each group of nasal drops was administered together at 50. mu.l/mouse, at a dose based on free base, and together at a body weight of 220 g/mouse, and the details are given in Table 2 below.
TABLE 2
6. Experimental methods
1) Rats were acclimatized pre-swim the day before dosing test. Placing the rat into the cavity
Swimming in a glass round jar with water depth of 20cm (water temperature 25 + -2 deg.C) for 15min per mouse, and one jar of water per mouse.
2) The drug intervention is started on the next day of the rat according to the table 2, the tested object group is slowly dripped into the nostrils at two sides by a liquid transfer machine according to the drug solution to be administered (25 mu L of each nostril at one side), and the drug administration position is kept for about 3s after the drug administration until the drug solution completely enters the nostrils. Swimming test trials were performed at 60min, 24h (day 2), 48h (day 3), 96h (day 5) post-dose, respectively, with a swimming duration of 5min, and the time for each mouse to stop swimming at 5min was recorded and analyzed throughout the Noldus video analysis system.
7. Results of the experiment
The effect of immobility at time to stop swimming within 5min was counted for each group of mice (n 10, Mean ± SEM) recorded throughout the Noldus video analysis system, and the results are shown in table 3 below.
TABLE 3
Note: "+" represents p <0.05vs. vehicle control group
The results show that:
1) compared with a vehicle control group and a venlafaxine control group which is a positive drug, the time for stopping the rat from swimming is reduced by taking the medicine for 60min, and the time for stopping the rat from swimming is reduced by continuously maintaining the medicine after two times of continuous administration.
2) Compared with vehicle control group, the nasal drip group of 15mg/kg of (S) -ketamine hydrochloride is administered for 60min by single nasal drip, so that the time for stopping the swimming of rats is reduced, and the effect is basically disappeared in 24 h.
3) Compared with the vehicle control group, the nasal drip group of 7.5mg/kg of hydrochloric acid (R) -ketamine has the advantages that the single nasal drip administration for 60min to 24h reduces the time for the rat to stop swimming and move immovably, and the effect is basically disappeared at 48 h.
4) Compared with the nasal drop group of 7.5mg/kg of (R) -ketamine hydrochloride and 15mg/kg of (S) -ketamine hydrochloride, the single nasal drop administration for 60min is equivalent to reduce the time for the rat to stop swimming.
5) Compared with the vehicle control group, the nasal drip group with 15mg/kg of (R) -ketamine hydrochloride and the nasal drip group with 30mg/kg of (R) -ketamine hydrochloride have the advantages that the time for stopping the swimming of the rat is reduced by dripping the nasal drip for 60min to 24h once, and the effect of reducing the time for stopping the swimming of the rat is still maintained by the nasal drip group with 30mg/kg of (R) -ketamine hydrochloride at 48 h.
6) Compared with nasal drops of 7.5mg/kg, 15mg/kg and 30mg/kg of (R) -ketamine hydrochloride, the (R) -ketamine hydrochloride has good dose-effect relationship on the effect and effect of reducing the immobility time of the rat in swimming.
7) Compared with a solvent control group, the nasal drip group of which the concentration of ketamine hydrochloride is 15mg/kg does not have the pharmacodynamic effect of reducing the time for the rat to stop swimming and move.
In conclusion, the (R) -ketamine hydrochloride has the effect of reducing the immobility time of the rat in swimming, and has a good dose-effect relationship with the effect, and under the nasal administration route, half dose of the (R) -ketamine hydrochloride can play the effect equivalent to the full dose of the (S) -ketamine hydrochloride.
The present invention is not limited to the above alternative embodiments, and other various forms of products can be obtained by anyone in light of the present invention. The above detailed description should not be taken as limiting the scope of the invention, which is defined by the appended claims, which are intended to be interpreted according to the breadth to which the description is entitled.
Claims (15)
- Use of R-ketamine or a salt thereof for the preparation of a nasal medicament for the treatment of depression, said nasal medicament having a lower dosing amount and/or active ingredient content than a nasally administered S-ketamine depression treatment medicament, in particular having a half dosing amount and/or active ingredient content than a S-ketamine depression treatment medicament, the nasal medicament preferably being in the form of nasal drops or nasal sprays and the salt of R-ketamine preferably being in the form of a hydrochloride salt.
- Use of R-ketamine or a salt thereof in the preparation of a nasal medicament for the treatment of depression, wherein in a single treatment, 14-56 mg of R-ketamine is administered, optionally 14-42 mg, preferably 25-45 mg or 28-42 mg of R-ketamine is administered, more preferably 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 42mg or 45mg of R-ketamine is administered, the nasal medicament is preferably in the form of nasal drops or nasal sprays, and the salt of R-ketamine is preferably in the form of a hydrochloride salt.
- 3. The use according to claim 2, wherein said nasal medicament is administered to any one nostril of the patient in a single dose for each treatment.
- 4. The use of claim 3, said nasal medication comprising an R-ketamine nasal spray that releases 14-56 mg, 14-42 mg, 25-45 mg, 28-42 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 42mg, or 45mg of R-ketamine per actuation.
- 5. The use according to claim 2, wherein said nasal medicament is administered to any nostril of the patient separately in two separate administrations per treatment.
- 6. The use of claim 5, wherein the nasal medication comprises R-ketamine nasal spray which releases 7-28 mg, 7-21 mg, 12.5-22.5 mg, 14-21 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg, 17.5-20 mg, 20-22.5 mg, 10mg, 12.5mg, 14mg, 15mg, 17.5mg, 20mg, or 22.5mg of R-ketamine per actuation.
- 7. The use of claim 4 or 6, wherein the R-ketamine nasal sprays are single dose formulations, each R-ketamine nasal spray containing the therapeutic agent required for a single treatment; or the R-ketamine nasal spray is a multi-dose preparation, and each R-ketamine nasal spray contains a therapeutic agent required by multiple treatments.
- Use of R-ketamine or a salt thereof in the preparation of a nasal medicament for the treatment of depression, wherein the nasal medicament is administered to a patient in an amount of 0.005-1.5 mg/kg, 0.005-0.75 mg/kg or 0.05-1.5 mg/kg, optionally 0.05-0.75 mg/kg or 0.065-0.265 mg/kg.
- 9. A transnasal medicament of R-ketamine for the treatment of depression which is as described in any one of claims 1 to 7.
- 10. The R-ketamine nasal drug of claim 9, comprising a drug label comprising R-ketamine nasal spray and 14-56 mg, 14-42 mg, 25-45 mg, 28-42 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40-45 mg, 42mg, or 45mg of R-ketamine administered to a patient in a single treatment under control using 1 or more of said R-ketamine nasal spray; optionally, the drug label further comprises a record that all the required therapeutic agents are administered to any nostril of the patient at one time or two or more times respectively in a single treatment.
- 11. The R-ketamine nasal medication of claim 10, wherein the R-ketamine nasal spray consists essentially of an R-ketamine solution and a nasal spray device, wherein the R-ketamine solution is formulated essentially of R-ketamine or a salt thereof, a pH buffer, a stabilizer, a pH adjusting agent, and water.
- 12. The R-ketamine nasal drug of claim 11, wherein the R-ketamine solution is formulated primarily from (R) -ketamine hydrochloride, citric acid, EDTA-2Na, sodium hydroxide, and water.
- 13. A method of treating depression, comprising nasally administering to a patient an effective amount of R-ketamine at each treatment, said effective amount being 14-56 mg, 14-42 mg, 25-45 mg, 28-42 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 42mg or 45 mg; the effective amount is especially 40-60 mg, 42-56 mg, 40mg, 42mg, 45mg, 56mg or 60mg for major depressive disorder patients with severe suicidal ideation or behavioral depression symptoms.
- 14. The method of claim 13, wherein following initial therapeutic administration of an effective amount of R-ketamine: administering an effective amount of R-ketamine 2 times a week for 1-4 weeks; administering an effective amount of R-ketamine 1 time per week for 5-8 weeks; on and after week 9, 1 effective amount of R-ketamine was administered weekly or 1 effective amount of R-ketamine was administered every 2 weeks.
- 15. The use according to any one of claims 1 to 8, the nasal medicament according to any one of claims 9 to 12 or the method according to any one of claims 13 to 14 wherein the depression is a treatment-resistant or a treatment-resistant depression.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110171062 | 2021-02-08 | ||
| CN2021101710629 | 2021-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114903840A true CN114903840A (en) | 2022-08-16 |
Family
ID=82762598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210103771.8A Pending CN114903840A (en) | 2021-02-08 | 2022-01-28 | Low-dose R-ketamine intranasal medicament for treating depression |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114903840A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107823195A (en) * | 2017-11-24 | 2018-03-23 | 无锡市精神卫生中心 | Application of the R ketamines in depression acute stages treated |
| CN110218157A (en) * | 2018-03-01 | 2019-09-10 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of R- ketamine and its officinal salt |
| CN111297803A (en) * | 2013-03-15 | 2020-06-19 | 詹森药业有限公司 | Pharmaceutical composition of S-ketamine hydrochloride |
| US20200405663A1 (en) * | 2017-09-27 | 2020-12-31 | National University Corporation Chiba University | R-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition functional disorder |
-
2022
- 2022-01-28 CN CN202210103771.8A patent/CN114903840A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111297803A (en) * | 2013-03-15 | 2020-06-19 | 詹森药业有限公司 | Pharmaceutical composition of S-ketamine hydrochloride |
| US20200405663A1 (en) * | 2017-09-27 | 2020-12-31 | National University Corporation Chiba University | R-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition functional disorder |
| CN107823195A (en) * | 2017-11-24 | 2018-03-23 | 无锡市精神卫生中心 | Application of the R ketamines in depression acute stages treated |
| CN110218157A (en) * | 2018-03-01 | 2019-09-10 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of R- ketamine and its officinal salt |
Non-Patent Citations (3)
| Title |
|---|
| KENJI HASHIMOTO: "Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine", BIOCHEMICAL PHARMACOLOGY, vol. 177, pages 1 - 8 * |
| LIJIA CHANG ET AL: "Comparison of antidepressant and side effects in mice after intranasal administration of (R, S)-ketamine, (R)-ketamine, and (S)-ketamine", PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOR, vol. 181, pages 53 - 59, XP085701063, DOI: 10.1016/j.pbb.2019.04.008 * |
| YAN WEI ET AL: "A historical review of antidepressant effects of ketamine and its enantiomers", PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOR, vol. 190, pages 1 - 9 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10278959B2 (en) | Ready to use ketorolac formulations | |
| US8093408B2 (en) | Antidepressant oral pharmaceutical compositions | |
| JP2007522249A (en) | Combination of an NMDA receptor antagonist and an antidepressant MAO inhibitor or GADPH inhibitor for the treatment of psychiatric conditions | |
| RU2552786C2 (en) | Liquid nasal spray containing low-dose naltrexone | |
| JPWO2007086493A1 (en) | Nasal medication | |
| JP2009137970A (en) | Pharmaceutical composition comprising mirtazapine and one or more selective serotonin reuptake inhibitor | |
| US8455667B2 (en) | Duloxetine compositions in the form of a powder for suspension in a liquid | |
| US20180042936A1 (en) | Maintenance therapy using tianeptine | |
| NO334247B1 (en) | Medication comprising roflumilast in combination with formoterol | |
| US4880833A (en) | Synergistic pharmaceutical compositions, their production and use | |
| US20230094778A1 (en) | Treatment of moderate and severe gastroparesis | |
| Elbaridi et al. | Current concepts of phenylpiperidine derivatives use in the treatment of acute and chronic pain | |
| CN114903840A (en) | Low-dose R-ketamine intranasal medicament for treating depression | |
| US20170087104A1 (en) | Medicament | |
| CA2893836A1 (en) | A combination medicament comprising phenylephrine and paracetamol | |
| AU2010295307B2 (en) | Phentermine liquid dosage form | |
| US11160799B2 (en) | Pediatric combination | |
| WO2022123607A1 (en) | Pharmaceutical formulations of esketamine | |
| EA011926B1 (en) | Oral antidepressant formulation comprising acetylsalicylic acid to accelerate onset of action | |
| CA2846768A1 (en) | Combinations comprising a s1p receptor modulator | |
| CN101138562A (en) | Pharmaceutical composition containing sertraline for treating melancholia and correlating diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: No. 566 Antaiwu Road, Gaoxin District, Chengdu, Sichuan Province, 611730 Applicant after: Sichuan Pu et Pharmaceutical Co.,Ltd. Address before: No.15 Gaopeng Avenue, high tech Zone, Chengdu, Sichuan 610093 Applicant before: Sichuan Pu et Pharmaceutical Co.,Ltd. |
|
| CB02 | Change of applicant information |